Adoptive immunotherapy against allogeneic kidney grafts in dogs with stable hematopoietic trichimerism.
Dogs given nonmyeloablative conditioning and marrow grafts from 2 dog leukocyte antigen (DLA)-identical littermate donors developed stable trichimerism and stably accepted a subsequent kidney graft from one of the marrow donors without the need for immunosuppression. In this study, we used trichimeras to evaluate strategies for adoptive immunotherapy to solid tumors, using the kidney as a tumor surrogate. Three DLA-identical trichimeric recipients were established by simultaneously infusing marrow from 2 DLA-identical donor dogs into a DLA-identical recipient conditioned with 2 Gy of total body irradiation (TBI) and given a short course of postgraft immunosuppression. After stable hematopoietic engraftment was confirmed, a kidney was transplanted from 1 of the 2 marrow donors into each respective trichimeric recipient. Peripheral blood lymphocytes from each kidney donor were then used to sensitize the alternate marrow donor. The trichimeric recipients were given donor lymphocyte infusions (DLIs) from the sensitized dogs and monitored for chimerism, graft-versus-host disease (GVHD), and kidney rejection. After DLI, we observed both prompt rejection of the transplanted marrow and donor kidney and disappearance of corresponding hematopoietic chimerism. Presumably due to shared minor histocompatibility antigens, host chimerism also disappeared, and GVHD in skin, gut, and liver developed. The native kidneys, although exhibiting lymphocytic infiltration, remained functionally normal. This study demonstrates that under certain experimental conditions, the kidney--an organ ordinarily not involved in graft-versus-host reactions--can be targeted by sensitized donor lymphocytes.
Graves
Scott S
SS
Clinical Research Division, Fred Hutchinson Cancer Research Center, Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98109-1024, USA. sgraves@fhcrc.org
Hogan
William J
WJ
Kuhr
Christian
C
Diaconescu
Razvan
R
Harkey
Michael
M
Sale
George E
GE
Stone
Brad
B
Georges
George E
GE
Storb
Rainer
R
D000818:Animals; D016026:Bone Marrow Transplantation; D004285:Dogs; D005260:Female; D006084:Graft Rejection / Q000209:etiology* / Q000276:immunology; D006085:Graft Survival / Q000276:immunology; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000009:adverse effects*; D016030:Kidney Transplantation; D017710:Lymphocyte Transfusion / Q000009:adverse effects*; D008297:Male; D018183:Transplantation Chimera / Q000276:immunology*; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
D015395:Histocompatibility Antigens Class I; C039692:histocompatibility antigen DLA